Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats

Abstract

Ketamine has a rapid, obvious, and persistent antidepressant effect, but its underlying molecular mechanisms remain unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of ketamine’s antidepressant effect. We investigated the alteration in miR-29b-3p in the brain of rats subjected to ketamine administration and chronic unpredictable mild stress (CUMS), and a sucrose preference test and forced swimming test were used to evaluate the rats’ depressive-like state. We used recombination adeno-associated virus (rAAV) or lentivirus-expressing miR-29b-3p to observe the change in metabotropic glutamate receptor 4 (GRM4). Cell culture and electrophysiological recordings were used to evaluate the function of miR-29b-3p. Ketamine dramatically increased miR-29b-3p expression in the prefrontal cortex of the normal rats. The dual luciferase reporter test confirmed that GRM4 was the target of miR-29b-3p. The miR-29b-3p levels were downregulated, while the GRM4 levels were upregulated in the prefrontal cortex of the depressive-like rats. The ketamine treatment increased miR-29b-3p expression and decreased GRM4 expression in the prefrontal cortex of the depressive-like rats and primary neurons. By overexpressing and silencing miR-29b-3p, we further validated that miR-29b-3p could negatively regulate GRM4. The silencing of miR-29b-3p suppressed the Ca2+ influx in the prefrontal cortex neurons. The miR-29b-3p overexpression contributed to cell survival, cytodendrite growth, increases in extracellular glutamate concentration, and cell apoptosis inhibition. The overexpression of miR-29b-3p by rAAV resulted in a noticeable relief of the depressive behaviors of the CUMS rats and a lower expression of GRM4. The miR-29b-3p/GRM4 pathway acts as a critical mediator of ketamine’s antidepressant effect in depressive-like rats and could be considered a potential therapeutic target for treating major depression disorder.

Anodal and cathodal tDCS modulate neural activity and selectively affect GABA and glutamate syntheses in the visual cortex of cats

“…2017; Wan et al . 2018), including the genes expression of GABAergic and glutamatergic markers (Ma et al . 2016; Zhang et al .…”

“…One possibility is that constant a-and c-tDCS form a downward and an upward current flow along axons of neurons arranged in vertical columns, respectively (Lund et al 2003;Douglas & Martin, 2004;Ohki et al 2005), which may preferentially affect the synthesis of neurotransmitters and thus produce directionally specific neurophysiology changes (Hannah et al 2019). For example, current flow in varied directions may differently affect the transmembrane transportation of Ca 2+ (Brosenitsch & Katz, 2001), which will initiate specific genes expression by activation of its transcription factors (Hardingham et al 1998;Ma et al 2014;Fukuchi et al 2015;Puri, 2020) or suppress some genes expression through microRNA-mediated post-transcriptional silence (Lee et al 2012;Rajgor et al 2017;Wan et al 2018), including the genes expression of GABAergic and glutamatergic markers (Ma et al 2016;Zhang et al 2018;Silva et al 2019). An alternative hypothesis is that a-and c-tDCS may respectively activate and inactivate glial astrocytes, as reported recently (Monai et al 2016), which can exert differential influence on GLU and GABA syntheses by affecting the GLN-GLU/GABA metabolic cycle (Jacob et al 2014;Walls et al 2015;Zheng et al 2016;Albrecht & Zielińska, 2017).…”

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

“…Furthermore, the treatment with an antagonist to miR‐448‐3p could diminish the antidepressant effects of ketamine in the LH paradigm, suggesting that the upregulation of miR448‐3p could have an antidepressant action . A new study has demonstrated that miR‐29b‐3p in the PFC plays a role in the antidepressant effects of ketamine in a CUMS model . Collectively, miRNA may play a role in the antidepressant effects; however, further detailed studies are needed to confirm this role.…”

Investigating the effects of chronic perinatal alcohol and combined nicotine and alcohol exposure on dopaminergic and non-dopaminergic neurons in the VTA

“…Its overexpression contributed to Ca2 + influx, neuron cell survival, an increase in the extracellular glutamate concentration, and an inhibition in the cell apoptosis. When miR-29b-3p was upregulated, it subsequently improved the depressive behaviors of depressed rats, which could be considered as a potential therapeutic target for treating major depression disorder 76 . Another study showed that miR-29b-3p has been speculated to serve as a potential biomarker for traumatic brain injury with a differential upregulation found in the plasma exosomes 77 .…”